The possibilities of use for clinical purposes of techniques for extracorporeal treatment of blood are extremely varied; they comprise a wide group of therapies which include intermittent or continuous renal support, apheresis and haemoperfusion treatment for removal of cytokines or toxins, the various techniques of extracorporeal support for the vital functions (known also as Extracorporeal Life Support or ECLS) including ExtraCorporeal Membrane Oxygenation or ECMO, veno-arterial for cardiac support or veno-venous for respiratory support, and the techniques for extracorporeal removal of carbon dioxide (ECCO2R).
All types of therapy entailing extracorporeal treatment of the blood also require the administration of an anticoagulant treatment, since the artificial surfaces are not able to reproduce the biocompatibility existing between blood and blood vessels. In the absence of this treatment, also known as scoagulation, the contact of the blood with the surfaces of the circuits causes activation of the coagulation cascade and leads to progressive thrombosis of the circuit with consequent loss of the extracorporeal support function and possible embolism of the thrombi.
The known strategies for scoagulating the blood in extracorporeal treatments are divided into systemic and regional: the former are aimed at scoagulating all the patient's blood; the latter are aimed at performing a scoagulation targeted only at the level of the extracorporeal circuit; each of the two strategies has advantages and disadvantages.
Systemic scoagulation is the strategy that has been used longest and is the most widespread; its main advantage is applicability to all the extracorporeal blood flow regimes, but it exposes the patient to an increased risk of bleeding. It is normally obtained by means of continuous parenteral infusion of unfractionated heparin, which guarantees a rapid on-set, a brief half-life, reversibility of the effect and low costs. The disadvantage of this drug is the poor predictability of the clinical effect and consequently the need for strict monitoring with laboratory tests; furthermore, it is not free from side effects such as heparin-induced thrombocytopenia.
To obtain systemic scoagulation, low molecular weight heparin is also used, administered by subcutaneous injections. It has a more predictable dose-effect relation than unfractionated heparin, but it does not allow monitoring of the anticoagulant effect.
Other systemic anticoagulants, such as the direct thrombin or X factor inhibitors, are used only rarely in the case of contraindications to heparin; they do not significantly reduce the risk of bleeding with respect to the heparin and they are more costly.
In recent years, to avoid the complications of systemic anticoagulant treatments, regional scoagulation techniques have been developed which limit the anticoagulant effect to the blood present only in the extracorporeal circuit.
One of these techniques entails the infusion of citrate immediately after the blood taken from the patient enters the extracorporeal circuit, which is then antagonised by the infusion of calcium chloride before returning the blood to the patient.
An alternative technique is to provide infusion of unfractionated heparin into the circuit, antagonised by the infusion of protamine before returning the blood to the patient.
The infusion of heparin-protamine is not widely used since, in addition to the known problems with the systemic administration of heparin, there are also problems due to the infusion of a drug, protamine, with a low therapeutic index, which has cardiovascular complications and can cause anaphylactic reactions.
Regional scoagulation obtained by infusion of citrate, on the other hand, is a technique which has become widespread in recent years. This technique is based on the capacity of the citrate anion to chelate the blood calcium, which represents an essential factor for functionality of the coagulation cascade. The citrate is infused at the beginning of the circuit mainly in the form of sodium citrate, while the calcium is re-infused at the end of the circuit in the form of calcium chloride, so that the blood returns to the patient with a normal coagulation functionality.
Examples of circuits in which citrate is used as an anticoagulant system are described in US2011168614 and US2011264025.
The main drawback of the use of citrate is the fact that the majority of the citrate infused reaches the systemic circulation of the patient and consequently must be eliminated by the patient by means of metabolisation (mainly hepatic).
Even when the patient has normal citrate clearance, and often this is not the case in critical patients, it is not possible to scoagulate extracorporeal blood flows higher than 200 ml/min since it would require doses of citrate higher than the patient's clearance capacity and consequently the citrate would accumulate in the patient, leading to severe side effects.
In addition to this problem, it is also difficult to control the concentration of the sodium administered as counter ion of the citrate, which is infused in the form of trisodium citrate.
Other systems for scoagulation of the extracorporeal blood are illustrated in DE102012020497 and WO2011130528. These systems provide a calcium removal unit positioned directly along the main line of the blood. One of the drawbacks associated with this configuration is the fact that to scoagulate a clinically significant entire blood flow, the device must have large dimensions, thus increasing the priming volume of the circuit. Furthermore, since the calcium removal system is positioned on the blood line, it has to be extremely biocompatible and in any case the blood upstream of the calcium removal unit is not coagulated. Lastly, when the calcium removal unit is an ionic resin, it is not possible to filter any fragments released by it into the blood since the latter cannot be filtered by appropriate fine mesh filters.
The need was therefore felt in the art to find an alternative strategy to obtain regional scoagulation of the blood which is free from the drawbacks of the known techniques.